PROJECT SUMMARY The goal of this proposal is to describe a 5-year plan to prepare Ashley Steed, MD, PhD, for independence as a physician-scientist studying the role of the microbiome in antiviral immunity. She graduated with distinction from Duke University with a degree in Biology and obtained her medical and research graduate degree from Washington University School of Medicine's Medical Scientist Training Program. After completing her residency and during her pediatric critical care fellowship, she joined Dr. Thaddeus Stappenbeck's laboratory, where she has demonstrated that elevated basal interferon type I signaling is protective to the host during influenza infection. This finding resolves a controversy in the influenza field. She has extended these studies to investigate the role of the enteric microbiome in driving systemic interferon levels and the consequences for viral infection. These findings serve as the basis for the aims in this proposal. Washington University School of Medicine is an exemplary location for Dr. Steed to develop her research platform with its longstanding history of NIH funded research and breadth and depth of resources. There is frequent crosstalk among departments, as Dr. Steed's mentoring committee and collaborators demonstrate, combining the expertise from the departments of Microbiology, Immunology, Pediatrics, and Medicine. Dr. Stappenbeck is a leader in the field of host-microbial interactions at mucosal surfaces; thus he is an ideal mentor for Dr. Steed because of his ability to decipher mechanisms of pathogenesis and his strong track record in training young scientists. His laboratory is a training hub of intellectual energy with a diverse group working on broad and creative projects. Dr. Steed will have multiple opportunities to present her work locally and in the larger scientific community. She will take graduate level classes to enhance her knowledge in microbiology and genomics and develop key technical skills with her collaborators. Dr. Steed's immediate goal is to fulfill the aims outlined in this proposal. While it is clear that the enteric microbiome is important for resistance to influenza pathogenesis, molecular understanding of this interaction remains obscure. She recently discovered a microbially-associated metabolite, desaminotyrosine, that enhances type I interferon signaling. This finding suggests that a specific microbial metabolite may mediate the protective effect of the microbiome. By completing the proposed aims, Dr. Steed will 1) test the hypothesis that desaminotyrosine protects from influenza pathogenesis by enhancing systemic interferon signaling, 2) define the mechanism by which desaminotyrosine augments interferon signaling, and 3) identify components of the microbiome that produce desaminotyrosine. Her laboratory's initial focus will be to further delineate these mechanisms such that insight from her research will translate to strategies aimed at improving resistance to viral pathogenesis and enhancing antiviral immunity.